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One-shot NMR analysis of microbial secretions identifies highly potent proteasome inhibitor

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Publication date 2012
Author Stein ML, Beck P, Kaiser M, Dudler R, Becker CFW, Groll M,
Project Structure, function and biosynthesis of syrbactins
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Original article (peer-reviewed)

Journal PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume (Issue) 109(45)
Page(s) 18367 - 18371
Title of proceedings PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Abstract

Natural products represent valuable lead structures for drug discovery. However, for most bioactive compounds no cellular target is yet identified and many substances predicted from genome analysis are inaccessible due to their life-stage dependent biosynthesis, which is not reflected in common isolation procedures. In response to these issues an NMR based and target directed protease assay for inhibitor detection of the proteasome was developed. The methodology is suitable for one-shot identification of inhibitors in conglomerates and culture broths. The technique was applied for analysis of the different life-stages of the bacterium P. luminescens, which resulted in the isolation and characterization of cepafungin I (CepI), the strongest proteasome inhibitor described to date. Its biosynthesis is strictly regulated and solely induced by the specific environmental conditions determined by our methodology. The transferability of the developed technique to other drug targets may disclose an abundance of novel compounds applicable for drug development.
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